Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium
Yeung, Edwina; Biedrzycki, Richard J; Gómez Herrera, Laura C; Issarapu, Prachand; Dou, John; Marques, Irene Fontes; Mansuri, Sohail Rafik; Page, Christian Magnus; Harbs, Justin; Khodasevich, Dennis; Poisel, Eric; Niu, Zhongzheng; Allard, Catherine; Casey, Emma; Berstein, Fernanda Morales; Mancano, Giulia; Elliott, Hannah R; Richmond, Rebecca; He, Yiyan; Ronkainen, Justiina; Sebert, Sylvain; Bell, Erin M; Sharp, Gemma; Mumford, Sunni L; Schisterman, Enrique F; Chandak, Giriraj R; Fall, Caroline H D; Sahariah, Sirazul A; Silver, Matt J; Prentice, Andrew M; Bouchard, Luigi; Domellof, Magnus; West, Christina; Holland, Nina; Cardenas, Andres; Eskenazi, Brenda; Zillich, Lea; Witt, Stephanie H; Send, Tabea; Breton, Carrie; Bakulski, Kelly M; Fallin, M Daniele; Schmidt, Rebecca J; Stein, Dan J; Zar, Heather J; Jaddoe, Vincent W V; Wright, John; Grazuleviciene, Regina; Gutzkow, Kristine Bjerve; Sunyer, Jordi; Huels, Anke; Vrijheid, Martine; Harlid, Sophia; London, Stephanie; Hivert, Marie-France; Felix, Janine; Bustamante, Mariona; Guan, Weihua (2024-05-29)
Wiley-Blackwell
29.05.2024
Yeung, E. , Biedrzycki, R. J. , Gómez Herrera, L. C. , Issarapu, P. , Dou, J. , Marques, I. F. , Mansuri, S. R. , Page, C. M. , Harbs, J. , Khodasevich, D. , Poisel, E. , Niu, Z. , Allard, C. , Casey, E. , Berstein, F. M. , Mancano, G. , Elliott, H. R. , Richmond, R. , He, Y. , … Guan, W. (2024). Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium. Aging Cell, 23, e14194. https://doi.org/10.1111/acel.14194
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© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
https://creativecommons.org/licenses/by/4.0/
© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
https://creativecommons.org/licenses/by/4.0/
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202405304084
https://urn.fi/URN:NBN:fi:oulu-202405304084
Tiivistelmä
Abstract
Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5–10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10−8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.
Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5–10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10−8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.
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